Spinal Cord Injury Therapeutic Targeting from Acute Phase to Subacute Phase

The present disclosure relates to a therapeutic agent for spinal cord injury from an acute phase to a subacute phase, in particular, a therapeutic agent for severe spinal cord injury. The present disclosure also relates to a motor dysfunction-alleviating agent for spinal cord injury from an acute phase to a subacute phase (in particular, a lower limb motor function improver, a walking ability improver, or a walking ability-acquiring agent), an inhibitor for spinal cord cavitation in a lesion site of a spinal cord, an inhibitor for atrophy of an injured spinal cord, an inhibitor for demyelination after spinal cord injury, an improver for remyelination after spinal cord injury, a promoter for migration/axon elongation in a lesion site of a spinal cord, and a method of increasing a survival and engraftment rate of pluripotent stem cells for transplantation.

The respective agents of the present disclosure are sometimes collectively referred to as “agents of the present disclosure.”

The present application claims priority from Japanese Patent Application No. 2022-143261, the disclosure of which is incorporated herein by reference.

Spinal cord injury is a disease state showing the paralysis of sensory, motor, and autonomic nervous systems below a lesion with the injury of a spinal cord parenchyma by a trauma or the like as a trigger, and the total number of the patients of the injury in Japan has reached 150,000 or more. Further, about 5,000 new patients are occurring every year.

However, it has been considered that the central nervous system of a mammal is not regenerated once the system is injured, and hence under the current circumstances, no effective therapeutic method has been established yet.

A hepatocyte growth factor (hereinafter sometimes abbreviated as “HGF” in this description) protein was discovered as a bioactive protein having growth-promoting activity on a mature hepatocyte. As a result of subsequent investigations, it has been known that the HGF protein acts on the c-Met receptors of many cells, such as an epithelial cell and a vascular endothelial cell, as well as a hepatocyte, to be involved in the damage repair and regeneration of tissues and organs. The HGF protein can be produced in a large amount as a recombinant protein by a bioengineering approach, and the recombinant HGF protein has been expected to be applied as a therapeutic agent not only for hepatitis and liver cirrhosis but also for a renal disease, a wound, or the like.

Meanwhile, many investigations in the expression and functional analysis of a gene including a recent knock-out/knock-in mouse approach have revealed that the HGF protein also has promoting actions on the survival of a nerve cell and the elongation of a neurite, and is hence a factor important as a neurotrophic factor.

The HGF protein shows neurotrophic factor activity on each of nerve cells, such as a hippocampal neuron, a dopaminergic neuron, a cerebellar granule cell, a sensory neuron, and a motor neuron. The HGF protein shows a strong survival-promoting action particularly on the motor neuron, and the activity is comparable to the activity of a glial cell line-derived neurotrophic factor (GDNF) known to have the strongest survival-promoting action on the motor neuron.

It has been reported that the HGF protein may be used as a therapeutic agent for various nerve diseases including amyotrophic lateral sclerosis (ALS) and spinal cord injury on the basis of such neurotrophic activity (see Patent Literature 1).

In Non Patent Literature 1, there is a disclosure “that the administration of a hepatocyte growth factor and an iPS cell-derived NSC after spinal cord injury is assumed to be effective in regeneration after the spinal cord injury.” However, there is no disclosure or suggestion of the configuration of each of the agents of the present disclosure.

In Non Patent Literature 2, there is a disclosure of a “therapeutic method including applying a gelatin-furfurylamine (FA) hydrogel and a CBD-HGF or a HGF in combination to an animal whose spinal cord has been injured by compression.” However, there is no disclosure or suggestion of the configuration of each of the agents of the present disclosure.

In Patent Literature 2, there is a disclosure of a “columnar HGF protein-containing sustained release preparation obtained by mixing an aqueous solution of a HGF protein and a solution of atelocollagen in a phosphate buffer, then freeze-drying the mixture, and subjecting the dried product to compression molding.” However, there is no disclosure or suggestion of the configuration of each of the agents of the present disclosure.

In Patent Literature 3, there is a disclosure of a “therapeutic agent for nerve injury including a differentiated cell-derived pluripotent stem cells.” However, there is no disclosure or suggestion of the configuration of each of the agents of the present disclosure.

An object of the present disclosure is to provide a therapeutic agent for spinal cord injury from an acute phase to a subacute phase that has heretofore been difficult to treat, in particular, severe spinal cord injury. Another object of the present disclosure is to provide a therapeutic agent applicable even to severe spinal cord injury on which a sufficient effect is not obtained with a HGF alone or an iPS alone, for example, as follows: load walking cannot be performed.

The inventors of the present disclosure have recognized that an agent including the following (1) and (2) has a therapeutic effect and a motor dysfunction-alleviating effect on severe spinal cord injury from an acute phase to a subacute phase, in particular, severe spinal cord injury on which no effect is obtained with a HGF alone or an iPS alone, and thus the inventors have completed the present disclosure:

The present disclosure includes the following.

1. A therapeutic agent for spinal cord injury from an acute phase to a subacute phase, including the following:

2. The therapeutic agent according to Item 1, wherein the pluripotent stem cells are an iPS cell-derived neural stem cell and/or neural progenitor cells.

3. The therapeutic agent according to Item 1, wherein the spinal cord injury is severe spinal cord injury.

4. The therapeutic agent according to Item 1, wherein the substance having a c-Met phosphorylation action is a hepatocyte growth factor protein, the pluripotent stem cells are an iPS cell-derived neural stem cell and/or neural progenitor cells, and the spinal cord injury from the acute phase to the subacute phase is severe spinal cord injury.

5. The therapeutic agent according to Item 4, wherein the hepatocyte growth factor protein is intrathecally administered.

6. The therapeutic agent according to Item 5, wherein the hepatocyte growth factor protein is administered into a subarachnoid cavity.

7. The therapeutic agent according to any one of Items 1 to 6, wherein the treatment is promotion of regeneration of an injured spinal cord and/or alleviation of an accessory symptom accompanying the spinal cord injury.

8. The therapeutic agent according to Item 7, wherein the promotion of the regeneration of the injured spinal cord is promotion of axon extension, inhibition of atrophy of the spinal cord, an increase in survival and engraftment rate of the pluripotent stem cells, inhibition of demyelination, an improvement in remyelination, and/or inhibition of spinal cord cavitation.

9. The therapeutic agent according to Item 7, wherein the promotion of the regeneration of the injured spinal cord is activation of an endogenous nerve cell, reconstruction of a neural network, and/or promotion or encouragement of an increase in number of functional nerve fibers.

10. The therapeutic agent according to Item 7, wherein the accessory symptom accompanying the injured spinal cord is motor dysfunction.

11. The therapeutic agent according to Item 10, wherein the motor dysfunction is motor dysfunction of a lower limb.

12. The therapeutic agent according to Item 11, wherein the motor dysfunction is walking ability loss.

13. A therapeutic agent for spinal cord injury from an acute phase to a subacute phase, including a hepatocyte growth factor protein,

14. A therapeutic agent for spinal cord injury from an acute phase to a subacute phase, including an iPS cell-derived neural stem cell and/or neural progenitor cells,

15. A motor dysfunction-alleviating agent for spinal cord injury from an acute phase to a subacute phase, including the following:

16. The motor dysfunction-alleviating agent according to Item 15, wherein the motor function is a lower limb motor function or a walking function.

17. An inhibitor for demyelination after spinal cord injury for spinal cord injury from an acute phase to a subacute phase, including the following:

18. An improver for remyelination after spinal cord injury for spinal cord injury from an acute phase to a subacute phase, including the following:

19. An inhibitor for spinal cord cavitation for spinal cord injury from an acute phase to a subacute phase, including the following:

20. An inhibitor for atrophy of a spinal cord for spinal cord injury from an acute phase to a subacute phase, including the following:

21. A promoter for axon elongation in a lesion site for spinal cord injury from an acute phase to a subacute phase, including the following:

22. A promoter for reconstruction of a neural network of a lesion site and/or an increase in number of functional never fibers thereof for spinal cord injury from an acute phase to a subacute phase, including the following:

23. A therapeutic method for spinal cord injury from an acute phase to a subacute phase, including the following steps:

24. A kit for treating spinal cord injury from an acute phase to a subacute phase, including the following:

25. A method of increasing a survival and engraftment rate of pluripotent stem cells for transplantation, including bringing a hepatocyte growth factor into contact with the pluripotent stem cells for transplantation.

The agents of the present disclosure each have one or more of the following effects:

The targets of the present disclosure (agents of the present disclosure) each relate to a therapeutic agent for spinal cord injury from an acute phase to a subacute phase, in particular, a therapeutic agent for severe spinal cord injury. Above all, the agents may each be a therapeutic agent for severe spinal cord injury on which no effect is obtained with a HGF alone or an iPS alone. The present disclosure also relates to a motor dysfunction-alleviating agent for spinal cord injury from an acute phase to a subacute phase (in particular, a therapeutic agent for severe spinal cord injury, above all, severe spinal cord injury on which no effect is obtained with a HGF alone or an iPS alone) (in particular, a walking ability improver or a walking ability-acquiring agent), an inhibitor for spinal cord cavitation in a lesion site of a spinal cord, an inhibitor for atrophy of an injured spinal cord, and a promoter for migration/axon elongation in a lesion site of a spinal cord.

The agents of the present disclosure each include the following:

Each of the above-mentioned (a) and (b) is preferably intended for intrathecal administration or intraspinal administration. More specifically, it is more preferred that the above-mentioned (a) be intended for intrathecal administration, and the above-mentioned (b) be intended for intraspinal administration.

The present disclosure is also directed to the use of the above-mentioned (1) and/or the above-mentioned (2) in the production of a therapeutic agent for spinal cord injury, a motor dysfunction-alleviating agent, an inhibitor for demyelination after spinal cord injury, an improver for remyelination after spinal cord injury, an inhibitor for spinal cord cavitation, an inhibitor for atrophy of a spinal cord, a promoter for axon extension in a lesion site, and a promoter for reconstruction of a neural network and/or an increase in number of functional never fibers.

Although phases ranging from the acute phase to subacute phase of spinal cord injury may each serve as a target to be treated with each of the agents of the present disclosure, the agent may be preferably intended for the treatment of severe spinal cord injury that has been difficult to treat (in particular, the acquisition of a walking ability has been difficult) by a related-art therapeutic method.

The term “severe” means a patient who cannot perform lower limb loading.